Depression, anxiety, and other stress-related disorders are widespread psychological conditions with broad health implications, including negative impacts on cardiovascular and metabolic functions and on mental health, including memory dysfunction. The prevalence of depression is even higher in veterans. It was estimated that approximately 30% of Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) veterans are affected by depression. Current available treatments for depression mainly target the serotonergic and noradrenergic system and only produce temporary remission in less than 50% of patients with wide range of ?adverse? events. There is an urgent need for new therapeutics to treat specific underlying disease mechanisms that are not addressed by standard antidepressants. Stress-mediated synaptic maladaptation of nucleus accumbens (NAc) and induction of inflammatory cytokines in the periphery contribute to depression-like behaviors both in humans and in experimental models. Both peripheral inflammation and synaptic plasticity maladaptation have emerged as newly hypothesized clinical intervention targets for depression. We recently identified two phytochemicals, namely dihydrocaffeic acid (DHCA) and malvidin-3-O-glucoside (Mal-gluc) that are effective in preventing and treating depression in multiple experimental models of depression and in both males and females. We found DHCA reduces pro- inflammatory interleukin 6 (IL-6) generations by inhibiting DNA methylation at the CpG-rich IL-6 sequences introns 1 and 3, while Mal-gluc modulates synaptic plasticity by increasing histone acetylation of the regulatory sequences of the Rac1 gene. By simultaneously targeting peripheral inflammation and synaptic maladaptation, DHCA and Mal-gluc synergistically promote resilience against stress-induced depression phenotypes including social isolation, anhedonia, self-neglect and anxiety in animal models of depression. In vitro toxicity and drug- like properties studies have shown that both compounds are deemed to be safe and have acceptable drug-like properties. In vivo safety studies also showed that 2-week treatment with DHCA with dose 10 times higher than the efficacious dose, and Mal-gluc with dose 100 times higher than the efficacious dose, did not lead to any adverse toxicity in mice. Based on these evidence, the overall goal of the Merit application is to conduct a thorough pharmacology and toxicology studies to gather sufficient pharmacological and safety information of the two lead compounds. Specifically, we propose to conduct oral bioavailability studies, pharmacokinetics and toxicokinetics studies on single oral dose, 4-week subchronic and 6-month chronic treatment of the two compounds either provided individually or in combination. The information gathered from the proposed studies will provide critical data required by the FDA for moving forward to translational application of the two compounds in human Phase I clinical studies. Our approaching to target inflammation and synaptic maladaptation is particularly important for those depression patients who are resistant to current depression medications, especially among the majority of patients who are characterized by high plasma levels of IL-6. Because neither DHCA nor Mal-gluc effectively interacts with monoaminergic systems that are targeted by conventional antidepressants, DHCA/Mal-gluc can be safely used as add-on with currently available antidepressants to simultaneously target multiple disease mechanisms and increase the likelihood of therapeutic success. The treatment intervention being investigated in this application may significantly improve the health and lives of veterans affected by the stress disorders including depression, anxiety disorders and posttraumatic stress disorders (PTSD).